Recent advances in genomics and proteomics techniques have allowed the interrogation of the genome/proteome to identify novel mechanisms underlying disease etiology. Ultimately such interrogations would encompass the complete chemical space of the cell, including endogenous small molecules or metabolome. An example that illustrates these challenges is the regulation of nociception. Conditions such as inflammation are known to sensitize our sense of touch and temperature such that non-noxious conditions become painful (allodynia) and noxious conditions become more painful (hyperalgesia). A prominent mechanism proposed to mediate this sensitization is the release of inflammatory mediators at the site of inflammation. This so- called inflammatory soup contains both proteinous as well as small molecular chemicals that are thought to sensitize ion channels expressed on nociceptive sensory neurons. Several ion channels of the transient receptor potential (TRP) family are known to function as sensors for temperature and a variety of structurally diverse chemicals that include pungent plant products such as capsaicin and mustard oil. Surprisingly however, only few endogenous ligands are known to date. The goal of this proposal is to establish an unbiased metabolome-wide approach for the identification of endogenous channel and receptor agonists. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to establish an unbiased metabolome-wide approach for the identification of endogenous activators of thermoTRPs involved in pain sensation.